Pharmaceutical compositions of tricyclic AKR1C3-dependent KARS inhibitors and methods for producing the same

Abstract

The present invention relates to solid-phase pharmaceutical compositions of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, which is useful as an AKR1C3-dependent KARS inhibitor. The present invention also relates to a process for preparing the pharmaceutical compositions of the compound, methods for using the pharmaceutical compositions in the treatment of various diseases and disorders, and their use in diseases and disorders mediated by AKR1C3-dependent KARS inhibitors.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions of 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, which is useful as an AKR1C3-dependent KARS inhibitor. The present invention also relates to a process for preparing the pharmaceutical compositions of the compound, methods for using the pharmaceutical compositions in the treatment of various diseases and disorders, and their use in diseases and disorders mediated by AKR1C3-dependent KARS inhibitors. [Background technology]

[0002] The NFE2L2 / NRF2-KEAP1 pathway has a strong genetic basis in cancer. TCGA sequence analysis reported that this pathway is altered in 34% of squamous cell lung cancers (Hammerman PS et al. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519-525 (2012)). Furthermore, TCGA and other groups have reported significant mutations in this pathway in other solid tumor indications, including head and neck squamous cell carcinoma and hepatocellular carcinoma. Aberrant activation of the NRF2 pathway can occur through gain-of-function genetic alterations in NRF2 or loss-of-function genetic alterations in KEAP1 or CUL3, which lead to stabilization of NRF2 and increased expression of target genes. When transcription of these target genes is deregulated, cancer cells become malignant and benefit from protection against oxidative stress, chemotherapy, and radiation therapy (Jaramillo MC, Zhang DD. The emerging role of the Nrf2-Keap1 signaling pathway in cancer Genes Dev. 27, 2179-2191 (2013)). Decreased NRF2 activity in tumors is associated with poor prognosis (Shibata T, Ohta T, Tong KI, Kokubu A, Odogawa R, Tsuta K, Asamura H, Yamamoto M, Hirohashi S. Cancer-related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci USA 105, 13568-13573 (2008)). To our knowledge, there are currently no approved therapies that selectively target cancers with genetic alterations in the NRF2 / KEAP1 pathway, representing an unmet medical need.

[0003] Aldehyde ketoreductase 1C3 (AKR1C3) is one of many target genes of the transcription factor NRF2, and its expression is elevated in NRF2 / KEAP1-mutated cancers (MacLeod AK, Acosta-Jimenez L, Coates PJ, McMahon M, Carey FA, Honda T, Henderson CJ, and Wolf CR. Aldo-keto reductases are biomarkers of NRF2 activity and are coordinately overexpressed in non-small cell lung cancer. Br J Cancer 115, 1530-1539 (2016)). AKR1C3 (also known as type 2 3α(17β)-hydroxysteroid dehydrogenase) is an NADP(H)-dependent ketosteroid reductase and a member of the aldo-keto reductase (AKR) superfamily, which plays a role in steroid hormone metabolism and signaling, as well as xenobiotic detoxification. Substrates of AKR1C3 include the endogenous substrates 5α-dihydrotestosterone, Δ4-androstene-3,17-dione, and progesterone (Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, Moore M, Palackal N, Ratnam K. Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem. J. 351, 67-77 (2000)), as well as the synthetic prodrug coumberone (Halim M, Yee DJ, Sames D.Imaging Induction of Cytoprotective Enzymes in Intact Human Cells:Coumberone,a Metabolic Reporter for Human AKR1C Enzymes Reveals Activation by Panaxytriol,an Active Component of Red Ginseng J.Am.Chem.Soc.130,14123-14128(2008)), PR104(Jamieson SM,Gu Y,Manesh DM,El-Hoss A novel fluorometric assay for aldo-keto reductase 1C3 predicts metabolic activation of the nitrogen mustard prodrug PR-104A in human leukaemia Cells. Biochem Pharmacol. 88, 36-45 (2014)) and TH3424 / OBI3424 (Threshold Pharmaceuticals International Publication No. 2016 / 145092 A1 brochure). We report the identification of tricyclic ketone compounds that are converted by AKR1C3 in the presence of NADPH into inhibitors of lysine t-RNA synthetase (KARS). Lysine t-RNA synthetase is part of a multi-tRNA synthetase complex and is a ubiquitous enzyme essential for protein synthesis.

[0004] AKR1C3-dependent KARS inhibitors have been shown to be effective in NRF2 / KEAP1 mutant cancers, as well as other types of cancers that have been reported to overexpress AKR1C3 (Guise CP, Abbattista MR, Singleton RS, Holford SD, Connolly J, Dachs GU, Fox SB, Pollock R, Harvey J, Guilford P, Donate F, Wilson WR, Patterson AV. The bioreductive prodrug PR-104A is activated under aerobic conditions by human aldo-keto reductase 1C3. Cancer Res. 70, 1573-1584 (2010)), such as breast cancer (Lewis MJ, Wiebe JP, Heathcote JG. Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2) is altered in human breast cancer). This provides an attractive strategy for selectively treating tumors that overexpress AKR1C3 compared to normal tissues, such as carcinoma. BMC Cancer 4, 27 (2004)) and prostate cancer (Fung KM, Samara ENS, Wong C, Metwalli A, Krlin R, Bane B, Liu CZ, et al. Increased expression of type 2 3α-hydroxysteroid dehydrogenase / type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma. Endocr Relat Cancer 13, 169-180 (2006)).

[0005] 6'-Fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, first disclosed in WO / 2021 / 005586, is a selective AKR1C3 reductase-dependent KARS inhibitor. There remains a need in the art for novel compositions for delivering AKR1C3 reductase KARS inhibitors and methods for using same to treat diseases associated with selective AKR1C3 reductase-dependent KARS inhibitors, which are stable and offer optimal availability. Summary of the Invention

[0006] The pharmaceutical compositions of the present disclosure and compositions thereof have now been found to be useful for, and exhibit desirable properties for, administration to patients in need of a selective AKR1C3 inhibitor. Generally, the pharmaceutically acceptable compositions disclosed herein are useful for treating or lessening the severity of various diseases or disorders, as described in detail herein. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 shows the desupersaturation profile of Compound (I) in FaSSIF-V1 when added as a DMSO solution at drug loadings of 100-2000 ppmw. [Figure 2] FIG. 10 is a diagram showing the pressure molding characteristics of the NSG table. [Figure 3] FIG. 1 shows two-step dissolution of HPMC-AS based ASG, FaSSGF→FaSSIF-V1 switch after 60 min, and a final drug loading of 100 ppmw. DETAILED DESCRIPTION OF THE INVENTION

[0008] The present disclosure is based, at least in part, on the identification of compounds that inhibit AKR1C3 and methods of using the same to treat diseases associated with AKR1C3. Disclosed herein is Compound (I) and pharmaceutical compositions thereof. [ka] The compound of formula (I), 6'-fluoro-N-(4-fluorobenzyl)-4'-oxo-3',4'-dihydro-1'H-spiro[piperidine-4,2'-quinoline]-1-carboxamide, is active in a variety of assays and therapeutic models and acts as a selective AKR1C3 inhibitor. It would be desirable to provide pharmaceutically acceptable compositions comprising Compound (I) that confer properties such as improved stability, improved oral bioavailability, and low toxicity risk. Accordingly, the present disclosure provides pharmaceutical compositions of Compound (I).

[0009] In one aspect, the present invention provides a compound of formula (I) [ka] 1. A pharmaceutical composition of a compound of formula (I) comprising a compound of formula (I) stabilized in an amorphous state with a polymer.

[0010] Composition of Amorphous Spray Granules (ASG) In one aspect, the present invention provides a pharmaceutical composition for oral administration of Compound (I) to a subject, wherein Compound (I) is formulated as an amorphous spray granule. In some embodiments, the pharmaceutical composition of the present invention comprises: A pharmaceutical composition of a compound of formula (I), comprising: [ka] (i) An intragranular blend, (a) Amorphous spray granulation, (i) a compound of formula (I), wherein the compound exists in amorphous form; and (ii) a polymer; and (b) a suspending agent; (c) an intragranular blend comprising a carrier; and (ii) an extragranular blend, (d) one or more excipients; (e) a disintegrant; (f) a glidant; (g) a lubricant; and an extragranular blend comprising:

[0011] Nanospray Granule (NSG) Composition In one aspect, the present invention provides a pharmaceutical composition for oral administration of Compound (I) to a subject, wherein Compound (I) is formulated as a nanospray granulation. In some embodiments, the present invention provides a pharmaceutical composition for oral administration of Compound (I) to a subject, wherein Compound (I) is formulated as a nanospray granulation. [ka] The pharmaceutical composition of the compound represented by (i) nano-sized crystalline spray granules, (a) a compound of formula (I) in crystalline form A, wherein the crystals are nanosized; (b) a polymer; (c) a surfactant; (d) nano-sized crystalline spray granules comprising a carrier; and (ii) an extragranular blend, (e) one or more excipients; (f) a disintegrant; (g) a glidant; and (h) a lubricant, and an extragranular blend comprising:

[0012] A. Compound (I) As defined above, the pharmaceutical composition of the present invention is an amorphous spray granulation or nanospray granulation containing Compound (I). Compound (I) can be prepared according to Example 40 of International Publication No. WO / 2021 / 005586, which is incorporated herein by reference.

[0013] In some embodiments, the crystalline solid of Compound (I) is anhydrous Form A of Compound (I). In some embodiments, Form A of Compound (I) is a form having at least 1, 2, 3, 4, or 5 powder X-ray diffraction peaks set forth in Table 1 below.

[0014] [Table 1]

[0015] In another aspect of the above embodiment, crystalline Form A of the compound of Formula (I) is characterized by having an X-ray powder diffraction pattern, measured at a temperature of about 25° C., comprising two or more 2θ values selected from the group consisting of 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ, and 31.7±0.2°2θ. In another aspect of the above embodiment, crystalline Form A of the compound of Formula (I) is characterized by having an X-ray powder diffraction pattern, measured at a temperature of about 25° C., comprising three or more 2θ values (CuKαλ=1.54184 Å) selected from the group consisting of 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ, and 31.7±0.2°2θ. In another aspect of the above embodiment, crystalline Form A of the compound of Formula (I) is characterized by having an X-ray powder diffraction pattern comprising four or more 2θ values selected from the group consisting of 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ, and 31.7±0.2°2θ, measured at a temperature of about 25°C. In another aspect of the above embodiment, crystalline Form A of the compound of Formula (I) is characterized by having an X-ray powder diffraction pattern, measured at a temperature of about 25° C., comprising five or more 2θ values selected from the group consisting of 9.6±0.2°2θ, 10.5±0.2°2θ, 13.4±0.2°2θ, 15.7±0.2°2θ, 17.1±0.2°2θ, 19.2±0.2°2θ, 21.0±0.2°2θ, 22.4±0.2°2θ, 27.3±0.2°2θ, 30.4±0.2°2θ, and 31.7±0.2°2θ.

[0016] In some embodiments, Compound (I) is present in the pharmaceutical composition in an amount of about 1% to about 40% by weight. In some embodiments, Compound (I) is present in the pharmaceutical composition in an amount of about 5% to about 20% by weight. In some embodiments, Compound (I) is present in the pharmaceutical composition in an amount of about 8% to about 14% by weight. In some embodiments, Compound (I) is present in the pharmaceutical composition in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight. In some embodiments, Compound (I) is present in the pharmaceutical composition in an amount of about 11.9% by weight. In another embodiment, Compound (I) is present in an amount of about 12.5% by weight. In further embodiments, Compound (I) is present in an amount of about 20-40% by weight. In some embodiments, Compound (I) is present in an amount of about 40% by weight.

[0017] Particle size distribution of nanosuspension The granule size of the nanosuspension granules is measured, for example, by laser diffraction (eg, particle size distribution (PSD)) using methods and equipment known to those skilled in the art.

[0018] According to the present invention, Compound (I) can be used directly or subjected to mechanical means to achieve an average particle size of less than 1000 nm. Particle size is measured, for example, by laser diffraction (e.g., particle size distribution (PSD)) using methods and equipment known to those skilled in the art. Preferably, the particle size, as measured by PCS, is less than 500 nm, more preferably less than 350 nm, and most preferably less than 250 nm. In one embodiment, the particle size of the suspension as measured by PCS is between about 50 nm and about 1000 nm, or between about 50 nm and about 500 nm, or between about 50 nm and about 350 nm, or between about 100 nm and about 170 nm, for example, the particle size is about 50 nm, or about 70 nm, or about 90 nm, or about 100 nm, or about 110 nm, or about 120 nm, or about 130 nm, or about 140 nm, or about 150 nm, or about 160 nm, or about 170 nm, or about 180 nm, or about 190 nm, or about 200 nm, or about 230 nm, or about 250 nm, or about 280 nm, or about 300 nm, or about 320 nm, or about 350 nm, or about 370 nm, or about 400 nm, or about 450 nm, or about 500 nm. More preferably, the particle size is from about 100 nm to about 350 nm, or from about 110 nm to about 180 nm, or from about 250 nm to about 350 nm. The formed particles are stabilized by the presence of the polymer in the intragranular blend as defined herein, allowing the particles to be maintained at the desired size and in a stable state.

[0019] The API particles can be prepared by any suitable milling technique, such as jet milling, pin milling, wet ball milling, or the like, which are well known in the art.

[0020] B. Polymer As defined above, the pharmaceutical compositions of the present invention are amorphous spray granules or nanospray granules comprising a polymer. In some embodiments, the polymer comprises an organic polymer. Suitable polymers include cellulose or starch, microcrystalline cellulose (MCC), Avicel PH 101 (FMC BioPolymer), acacia, sodium alginate, gelatin, starch, pregelatinized starch, methylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene glycol, polyvinylpyrrolidone (PVP), polyvinyl acetate phthalate (PVAP), copolyvidone (e.g., Kollidon® VA 64), crospovidone (e.g., Kollidon® CL), e.g., Gelcarin GP. Examples of suitable polyacrylates include, but are not limited to, carrageenans such as ethylcellulose 812, and cellulose acetate, or polyacrylates such as ammonio methacrylate copolymer (Eudragit RS / RL), methacrylic acid-ethyl acrylate copolymer (Eudragit L100-55), polyvinyl acetate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), or combinations thereof.

[0021] In some embodiments, the polymer comprises hydroxypropyl methylcellulose (HPMC). In some further embodiments, the polymer comprises hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

[0022] In some embodiments, the polymer comprises polyvinylpyrrolidone (PVP). In some further embodiments, the polymer comprises polyvinylpyrrolidone 30 (PVP-30).

[0023] In some embodiments, the polymer is any amorphous carrier commonly utilized in formulating pharmaceutical compositions for oral administration.

[0024] In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 1% to about 40% by weight. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 15% to about 30% by weight. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 22% to about 28% by weight. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 8.34% by weight. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 16.67% by weight. In some embodiments, the polymer is present in the pharmaceutical composition in an amount of about 26.6% by weight.

[0025] C. Suspension As defined above, the pharmaceutical composition of the present invention is an amorphous spray granule or nanospray granule containing a suspending agent. In some embodiments, the suspending agent is any suspending agent commonly used in the formulation of pharmaceutical compositions for oral administration. In some embodiments, the pharmaceutical composition of the present invention contains a suspending agent selected from simethicone, silicon dioxide, silica, colloidal silica, magnesium silicate, magnesium trisilicate, talc, and other forms of silica, such as agglomerated silica and hydrated silica. In a further embodiment, the suspending agent is silicon dioxide.

[0026] D. Carrier As defined above, the pharmaceutical composition of the present invention is an amorphous spray granulation or nanospray granulation comprising a carrier.

[0027] In some embodiments, the carrier is any carrier commonly used in formulating pharmaceutical compositions for oral administration. In some embodiments, the pharmaceutical compositions of the present invention comprise a carrier selected from lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, including silicified microcrystalline cellulose, sodium saccharin, glucose, and / or glycine. In addition to those listed above, suitable tablet and / or capsule diluents in the present disclosure include, but are not limited to, calcium carbonate, calcium hydrogen phosphate, calcium phosphate, calcium sulfate, powdered cellulose, glucan binders, fructose, kaolin, starch, pregelatinized starch, compressible sugar, and confectioners' sugar, and combinations thereof. In further embodiments, the carrier is selected from lactose or mannitol and combinations thereof.

[0028] E. Excipients As defined above, the pharmaceutical composition of the present invention is an amorphous spray granulation or nanospray granulation comprising at least one excipient.

[0029] In some embodiments, the excipient is any excipient commonly used in formulating pharmaceutical compositions for oral administration. In some embodiments, the pharmaceutical compositions of the present invention comprise an excipient selected from known compatibilizers or excipients, such as cellulose derivatives, such as microcrystalline cellulose or lignocellulose (including microcrystalline cellulose and silicified microcrystalline cellulose), lactose, anhydrous lactose or lactose monohydrate, sucrose, starch, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), dextrose, mannitol (including Mannitol Pearlitol SD200), fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts, such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin / glucose binders, maltodextrin, compressible sugars, and / or mixtures of two or more thereof.

[0030] F. Disintegrants As defined above, the pharmaceutical composition of the present invention is an amorphous spray granulation or nanospray granulation containing a disintegrant.

[0031] In some embodiments, the disintegrant is any disintegrant commonly utilized in formulating pharmaceutical compositions for oral administration. In some embodiments, the pharmaceutical compositions of the present invention comprise a disintegrant selected from croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium carboxymethyl starch, sodium starch glycolate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl cellulose, and other known disintegrants. Several specific types of disintegrants are suitable for use in the formulations described herein. In addition to the disintegrants described above, disintegrants suitable for use in tablets of the present disclosure include, but are not limited to, alginic acid, polacoline potassium, sodium starch glycolate, and pregelatinized starch, as well as combinations thereof. In a further embodiment, the disintegrant is sodium carboxymethyl cellulose. In other embodiments, the disintegrant is low-substituted hydroxypropyl cellulose (L-HPC).

[0032] G. Glidants As defined above, the pharmaceutical composition of the present invention is an amorphous spray granulation or nanospray granulation containing a glidant.

[0033] In some embodiments, the glidant is any glidant commonly utilized in formulating pharmaceutical compositions for oral administration. In some embodiments, the pharmaceutical compositions of the present invention comprise a glidant selected from silica, colloidal silica, magnesium silicate, magnesium trisilicate, talc, and other forms of silica, such as associative silicates and hydrated silica.

[0034] H. Lubricants As defined above, the pharmaceutical composition of the present invention is an amorphous spray granulation or nanospray granulation containing a lubricant.

[0035] In some embodiments, the lubricant is any lubricant commonly utilized in formulating pharmaceutical compositions for oral administration. In some embodiments, the pharmaceutical compositions of the present invention comprise a lubricant selected from magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, glyceryl palmitostearate, palmitic acid, myristic acid, and hydrogenated vegetable oils and fats, as well as other known lubricants and / or mixtures of two or more thereof. In addition to the lubricants described above, other lubricants suitable for use in the tablets and / or capsules of the present disclosure include, but are not limited to, glyceryl behenate, light mineral oil, polyethylene glycol, hard refined stearic acid, and combinations thereof.

[0036] I. Surfactants As defined above, the pharmaceutical composition of the present invention is an amorphous spray granulation or nanospray granulation containing a surfactant.

[0037] In some embodiments, the surfactant is any surfactant commonly utilized in formulating pharmaceutical compositions for oral administration. In some embodiments, the pharmaceutical composition of the present invention comprises a surfactant selected from acacia, cholesterol, diethanolamine, glyceryl monostearate, lanolin alcohol, lecithin, mono- and di-glycerides, monoethanolamine, oleic acid, oleyl alcohol, poloxamer, polyoxyethylene 50 stearate, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 10 oleyl ether, polyoxyethylene 20 cetostearyl ether, polyoxyethylene 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, triethanolamine, emulsifying wax, and combinations thereof.

[0038] Pharmaceutical Composition As noted above, in some embodiments, the pharmaceutical composition is an amorphous spray granulation comprising:

[0039] Embodiments: 1. Formula (I) [ka] 1. A pharmaceutical composition of a compound of formula (I) comprising a compound of formula (I) stabilized in an amorphous state with a polymer.

[0040] 2. The pharmaceutical composition of embodiment 1, wherein the compound of formula (I) is present in about 5-80% by weight, about 10-50% by weight, about 25-40% by weight, or about 30% by weight.

[0041] 3. The pharmaceutical composition of embodiment 1, wherein the polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, povidone (PVP), copovidone (PVP VA 64), cellulose acetate, cellulose acetate phthalate, or polyacrylates such as, for example, ammonio methacrylate copolymers (e.g., Eudragit RS / RL), methacrylic acid-ethyl acrylate copolymers (e.g., Eudragit L100 or L100-55), polyvinyl acetate, polyvinyl acetate phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®).

[0042] 4. The pharmaceutical composition of embodiment 3, wherein the polymer is HPMC-AS-L, HPMC-AS-M, HPMC-AS-H, or Eudragit L.

[0043] 5. Formula (I) [ka] A pharmaceutical composition of a compound represented by the formula: (i) An intragranular blend, (a) Amorphous spray granules, (i) a compound of formula (I), wherein the compound exists in amorphous form; and (ii) a polymer; and amorphous spray granules comprising: (b) a suspending agent; (c) an intragranular blend comprising a carrier; and (ii) an extragranular blend, (d) an excipient; (e) a disintegrant; (f) a glidant; (g) a lubricant; and an extragranular blend comprising:

[0044] 6.(i) Intragranular blends, (a) Amorphous spray granules, (i) a compound of formula (I) present in amorphous form in an amount of about 5% to 20% by weight; (ii) about 10% to about 60% by weight of a polymer; and (b) about 0.5% to 2.0% by weight of a suspending agent; (c) an intragranular blend comprising a carrier in an amount of about 20% to about 80% by weight; (ii) an extragranular blend, (d) an excipient in an amount of about 10% to about 40% by weight; (e) a disintegrant in an amount of about 0% to about 5% by weight; (f) a glidant in an amount of about 0.5% to about 2.0% by weight; (g) a lubricant in an amount of about 0.5% to about 3.0% by weight, and an extragranular blend comprising:

[0045] 7.(i) Intragranular blends, (a) Amorphous spray granules, (i) a compound of formula (I) present in amorphous form in an amount of 11.9% by weight; (ii) about 26.6 wt. % of a polymer; and amorphous spray granules comprising: (b) about 1.3 wt. % of a suspending agent; (c) an intragranular blend comprising a carrier in an amount of about 30.3 wt.%; (ii) an extragranular blend, (d) an excipient in an amount of about 24.6% by weight; (e) a disintegrant in an amount of about 2.8% by weight; (f) a glidant in an amount of about 1.0 wt. %; (g) a lubricant in an amount of about 1.5% by weight, and an extragranular blend comprising:

[0046] 8. The pharmaceutical composition of any one of embodiments 5-7, wherein the polymer is hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

[0047] 9. The pharmaceutical composition of embodiment 8, wherein the hydroxypropyl methylcellulose acetate succinate is selected from hydroxypropyl methylcellulose acetate succinate grade L (HPMC-AS-L), hydroxypropyl methylcellulose acetate succinate grade M (HPMC-AS-M), and hydroxypropyl methylcellulose acetate succinate grade H (HPMC-AS-H).

[0048] 10. The pharmaceutical composition of embodiment 7, wherein the suspending agent is silicon dioxide.

[0049] 11. The pharmaceutical composition of embodiment 7, wherein the carrier is lactose.

[0050] 12. The pharmaceutical composition of embodiment 7, wherein the excipient is lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), or a combination thereof.

[0051] 13. The pharmaceutical composition of embodiment 7, wherein the disintegrant is croscarmellose sodium.

[0052] 14. The pharmaceutical composition of embodiment 7, wherein the glidant is silicon dioxide.

[0053] 15. The pharmaceutical composition according to embodiment 7, wherein the lubricant is sodium stearyl fumarate.

[0054] 16.(i) Intragranular blends, (a) Amorphous spray granules, (i) a compound of formula (I) present in amorphous form in an amount of 11.9% by weight; (ii) amorphous spray granules comprising hydroxypropyl methylcellulose acetate succinate in an amount of about 26.6% by weight; (b) about 1.3 wt. % silicon dioxide; (c) lactose in an amount of about 30.3% by weight; and (ii) an extragranular blend, (d) lactose and microcrystalline cellulose in an amount of about 24.6% by weight; (e) croscarmellose sodium in an amount of about 2.8% by weight; (f) silicon dioxide in an amount of about 1.0 wt. %; (g) about 1.5% by weight of sodium stearyl fumarate; and an extragranular blend comprising:

[0055] 17. The pharmaceutically acceptable composition of any one of embodiments 1-16, wherein the composition is in the form of a capsule or tablet.

[0056] 18. (i) Preparation of an amorphous spray granulation, comprising: (a) suspending a compound of formula (I), a polymer, and a suspending agent in an organic solution of acetone containing water; (b) mixing the suspension of (a) to form a dispersion of dissolved compound of formula (I); (c) spraying the dispersion of (b) onto a carrier in a fluid bed dryer to form amorphous spray granules; (ii) preparing an extragranular phase, the extragranular phase comprising: (d) an excipient; (e) a disintegrant; (f) a glidant; (g) a lubricant; (iii) blending the amorphous spray granules (i) with the extragranular phase (ii) to form the final blend.

[0057] 19. A method for producing a pharmaceutical composition according to embodiment 18, wherein the composition is filled into a capsule.

[0058] 20. A method for producing the pharmaceutical composition of embodiment 18, wherein the composition is compressed into a tablet.

[0059] 21. Gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, seminoma or dysseminoma germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, lung squamous cell carcinoma, glioblastoma, glioma, childhood glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilia-associated acute 21. A method of treating a disease selected from the group consisting of myeloid leukemia, lymphoblastic T-cell lymphoma, liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and non-small cell lung cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the composition of any one of embodiments 1-20.

[0060] 22. The method of embodiment 21, wherein the disease is non-small cell lung cancer (NSCLC).

[0061] 23. Gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, seminoma or dysseminoma germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, lung squamous cell carcinoma, glioblastoma, glioma, childhood glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic 21. Use of a composition according to any one of embodiments 1 to 20 for the preparation of a medicament for the treatment of a disease selected from the group consisting of leukemia, eosinophilia-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and non-small cell lung cancer.

[0062] 24. The use according to embodiment 23, wherein the disease is non-small cell lung cancer (NSCLC).

[0063] 25. Formula (I) [ka] A pharmaceutical composition of a compound represented by the formula: (i) nano-sized crystalline spray granules, (a) a compound of formula (I) in crystalline form A, wherein the crystals are nanosized; (b) a polymer; (c) a surfactant; (d) nano-sized crystalline spray granules comprising a carrier; and (ii) an extragranular blend, (e) one or more excipients; (f) a disintegrant; (g) a glidant; and (h) a lubricant; and a pharmaceutical composition comprising an extragranular blend comprising:

[0064] 26. (i) Nano-sized crystalline spray granules, the crystalline nanospray granules comprising: (a) a compound of formula (I) in nano-sized crystalline form A in an amount of about 5% by weight to about 20% by weight; (b) a polymer in an amount of about 5% to 20% by weight; (c) a surfactant in an amount of about 0.1% to 1.0% by weight; (d) a carrier in an amount of about 20% to 80% by weight; and nano-sized crystalline spray granules comprising the carrier; (ii) an extragranular blend, (e) one or more excipients in an amount of about 25% to 50% by weight; (f) a disintegrant in an amount of about 2% to 10% by weight; (g) a glidant in an amount of about 0.5% to about 2.0% by weight; (h) an extragranular blend comprising a lubricant in an amount of about 0.5% to about 2.0% by weight.

[0065] 27. (i) Nano-sized crystalline spray granules, the crystalline nanospray granules comprising: (a) a compound of formula (I) in nano-sized crystalline form A in an amount of 12.5% by weight; (b) a polymer in an amount of about 8.34%; (c) a surfactant in an amount of about 0.25 wt. %; (d) a carrier in an amount of about 28.9% by weight; and nano-sized crystalline spray granules comprising: (ii) an extragranular blend, (e) one or more excipients in an amount of about 40% by weight; (f) a disintegrant in an amount of about 6% by weight; (g) a glidant in an amount of about 1.5% by weight; (h) a lubricant in an amount of about 1.5% by weight.

[0066] 28. The pharmaceutical composition of any one of embodiments 25-27, wherein the polymer is povidone or copovidone.

[0067] 29. The pharmaceutical composition according to embodiment 28, wherein the povidone is PVP K30.

[0068] 30. The pharmaceutical composition according to embodiment 27, (i) Crystalline nanospray granules, (a) a compound of formula (I) in nano-sized crystalline form A in an amount of 12.5% by weight; (b) povidone in an amount of about 8.34%; (c) sodium lauryl sulfate in an amount of about 0.25% by weight; (d) a lactose carrier in an amount of about 28.9% by weight; and a crystalline nanospray granule comprising: (ii) an extragranular blend, (e) lactose and microcrystalline cellulose in an amount of about 40% by weight; (f) croscarmellose sodium in an amount of about 6% by weight; (g) silicon dioxide in an amount of about 1.5% by weight; (h) about 1.5% by weight of sodium steraryl fumarate; and an extragranular blend comprising:

[0069] 31. The pharmaceutical composition of any one of embodiments 25-30, wherein the crystal of the compound of formula (I), crystalline form A, has a median particle size (D50) of about 150-250 nm.

[0070] 32. The process comprises: (i) mixing a mixture comprising nanosized crystalline form A of the compound of formula (I), a polymer and a surfactant in a liquid medium; (ii) adding said mixture to a carrier to form a dry granulation.

[0071] 33. The process of embodiment 32, wherein step (i) is carried out in a wet-milling chamber.

[0072] 34. The process of embodiment 32 or 33, wherein the liquid medium is an aqueous solution.

[0073] 35. The process of any one of embodiments 32 to 34, wherein the mixture of step (i) is dispersed on a carrier and dried to form granules.

[0074] 36. A process according to any one of embodiments 32 to 35, further comprising preparing a final dosage form by blending the granules obtained from step (ii) with an extragranular phase, the extragranular phase comprising one or more excipients, disintegrants, glidants, and lubricants.

[0075] 37. The process of embodiment 36, wherein the final dosage form is encapsulated or tableted.

[0076] 38. A process according to embodiment 37, wherein the final dosage form is compressed into tablets and the resulting tablets are further film-coated.

[0077] 39. A process for preparing a suspension comprising mixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, or the free form thereof, at least one polymer, and optionally a surfactant, with a liquid medium.

[0078] 40. The process according to embodiment 39, wherein the suspension is subjected to wet-milling to reduce the size of the crystals of the compound of formula (I).

[0079] 41. The suspension of embodiment 40, wherein the crystals of the compound of formula (I) in the suspension have a median particle diameter (D50) of about 100 nm to 500 nm.

[0080] 42. The suspension of embodiment 41, wherein the crystals of the compound of formula (I) in the suspension have a median particle diameter (D50) of about 150 nm to 250 nm.

[0081] Methods for producing pharmaceutical compositions The compositions of the present invention may suitably be prepared by combining the ingredients as dry powders, e.g., dry granulating the ingredients of a tablet, capsule, or tablet mix, and optionally applying a film coating, e.g., a moisture barrier film, to the compressed tablet to produce a powder for reconstitution.

[0082] Uses of the Compounds and Pharmaceutically Acceptable Compositions As generally described above, Compound (I), and the pharmaceutically acceptable solid compositions thereof described herein, are AKR1C3 inhibitors. The AKR1C3 inhibitor compounds of the present disclosure may, in some embodiments, find use in inhibiting the activity of AKR1C3.

[0083] In one aspect, the present disclosure provides a method for treating an AKR1C3-mediated disease or disorder in a subject in need thereof. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein, i.e., a pharmaceutical composition comprising Compound (I). In some embodiments, the disease or disorder is lung cancer, bladder cancer, cervical cancer, esophageal cancer, head and neck cancer, kidney cancer, or liver cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC), lung adenocarcinoma, or lung squamous cell carcinoma. In some embodiments, the administration is oral.

[0084] In another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, i.e., a pharmaceutical composition comprising Compound (I), for use in treating a disease or disorder mediated by AKR1C3 in a subject in need thereof. In yet another aspect, the present disclosure provides a pharmaceutical composition as disclosed herein, i.e., a pharmaceutical composition comprising Compound (I), for the manufacture of a medicament for treating a disease or disorder mediated by AKR1C3 in a subject in need thereof. In some embodiments, the disease or disorder is lung cancer, bladder cancer, cervical cancer, esophageal cancer, head and neck cancer, kidney cancer, or liver cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC), lung adenocarcinoma, or lung squamous cell carcinoma.

[0085] As used herein, the term "treatment" is used interchangeably with the term "therapy" and refers to both 1) therapeutic procedures or measures that cure, slow, alleviate symptoms of, and / or halt the progression of a diagnosed pathological condition, disease, or disorder, and 2) preventative / prophylactic measures. Those in need of treatment may include those who already have a particular medical disease or disorder, as well as those who may eventually develop the disorder (i.e., those at risk or in need of preventative measures).

[0086] As used herein, the term "subject" refers to an individual or patient on whom the subject method is performed. Generally, the subject is a human, although as will be understood by those skilled in the art, the subject may also be an animal.

[0087] The terms "therapeutically effective amount," "effective dose," "therapeutically effective dose," "effective amount," and the like refer to an amount of a subject compound that elicits a biological or medical response in a tissue, system, animal, or human receiving the compound. Generally, the response is either an improvement in a patient's symptoms or a desired biological outcome. In some embodiments, such a compound should be sufficient to inhibit AKR1C3.

[0088] In some embodiments, the effective amount of the AKR1C3 inhibitor compound of the present invention is an amount ranging from about 10 mg to about 1000 mg. In further embodiments, the amount is ranging from about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, or about 500 mg to about 1000 mg. The dosage can be a single dose or a daily dose. In some embodiments, the effective amount of the AKR1C3 inhibitor compound is about 100 mg.

[0089] definition As used herein, the term "about," when used in connection with a quantity, refers to the stated value plus or minus 10% of said value. In some embodiments, "about" refers to the stated value plus or minus 5%, plus or minus 2%, or plus or minus 1% of said value.

[0090] As used herein, the terms "administer," "administering," and "administration" refer to any method, in sound medical practice, of delivering a provided composition, or an active agent contained therein, to a subject in a manner that provides a therapeutic effect.

[0091] As used herein, the phrase "effective amount" or "therapeutically effective amount" of an active agent or ingredient, or a pharmaceutically active agent or ingredient, refers to an amount of the pharmaceutically active agent sufficient to have a therapeutic effect upon administration. The effective amount of the pharmaceutically active agent will vary depending on the type of pharmaceutically active agent selected, the particular disease state or symptom being treated, the severity of the condition, the duration of treatment, the particular components of the composition used, and similar factors. Generally, the response will be either an improvement in the patient's symptoms or a desired biological result. In some embodiments, such an amount should be sufficient to inhibit c-kit kinase and treat a disease or disorder associated with c-kit kinase.

[0092] As used herein, the phrase "pharmaceutically acceptable salt" refers to a salt of a particular component that has the same activity as the unmodified compound and is biologically or otherwise objectionable. Salts can be formed with, for example, organic or inorganic acids. Suitable acids include acetic acid, acetylsalicylic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, bisulfonic acid, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecylsulfuric acid, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid, glycerophosphate, glycine, glucoheptanoic acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hemisulfonic acid, heptanesulfonic acid, and the like. Acids include hexanoic, hippuric, hydrobromic, hydrochloric, hydroiodic, hydroxyethanesulfonic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, naphthylansulfonic, naphthyl, nicotinic, nitrous, oxalic, pelargonic, phosphoric, propionic, saccharin, salicylic, sorbic, succinic, sulfuric, tartaric, thiocyanic, thioglycolic, thiosulfuric, tosylic, undecylenic, and amino acids of natural and synthetic origin.

[0093] As used herein, the term "preservative" refers to a known, pharmaceutically acceptable preservative that functions by inhibiting bacteria, fungi, yeast, mold, and other microorganisms and / or by inhibiting oxidation. Suitable preservatives include, but are not limited to, antimicrobial agents and / or antioxidants. Suitable antimicrobial agents may include, but are not limited to, benzoates, benzyl alcohol, sodium benzoate, sorbates, propionates, nitrites, and the like. Suitable antioxidants may include, but are not limited to, vitamin C, butylhydroxytoluene (BHT), sulfites, vitamin E, and the like. Other such preservatives for use in the present invention are described above and herein.

[0094] As used herein, the terms "prevent," "preventing," or "prevention" mean reducing, however slight, the predisposition or risk of a subject to develop a condition, disease, disorder, or symptom thereof. For purposes of prevention, the subject can be any subject, preferably one who is at risk of or predisposed to developing the condition, disease, or disorder. The term "prevention" includes preventing the onset of a clinically evident condition, disease, or disorder altogether, or preventing the onset of a condition, disease, or disorder that is not clinically evident in an at-risk individual. It also includes prophylactic treatment of subjects at risk of developing a condition, disease, or disorder.

[0095] As used herein, the term "solvent" refers to a pharmaceutically acceptable medium that is liquid at ambient temperature and in which one or more solutes can be dissolved or in which one or more substances can be partially dissolved or suspended. Numerous solvents are well known in the chemical and pharmaceutical arts and are described herein and below.

[0096] As used herein, the phrase "substantially pure" refers to a particular compound form that is substantially free from all other forms, degradation products of forms, and residual solvents, and is at least 85% pure by weight unless otherwise specified. A compound form can have at least 90% purity by weight, at least 93% purity by weight, at least 95% purity by weight, or at least 97%, 98%, 99%, or 99.5% purity by weight.

[0097] As used herein, "subject" or "individual" or "animal" or "patient" or "mammal" refers to any subject for whom diagnosis, prognosis, or treatment is desired, particularly a mammalian subject, such as a human.

[0098] As used herein, "treatment" or "treating" a disease, disorder, or condition includes alleviating at least one symptom thereof, reducing its severity, or slowing or inhibiting its progression. Treatment does not necessarily mean completely curing the disease, disorder, or condition. Compositions useful herein may be those that reduce the severity of the disease, disorder, or condition, reduce the severity of symptoms associated therewith, provide an improvement in the patient's or subject's quality of life, or delay or inhibit the onset of the disease, disorder, or condition.

[0099] Throughout this specification, when compositions are described as having, including, or comprising particular ingredients, or when processes and methods are described as having, including, or comprising particular steps, it is contemplated that there are additional compositions of the invention that consist essentially of, or consist of, the recited ingredients, and that there are processes and methods of the invention that consist essentially of, or consist of, the recited steps.

[0100] As used herein, all percentages are by weight of the total composition (ie, % by weight) unless otherwise specified.

[0101] Any concentration range, percentage range, or ratio range set forth herein, unless otherwise indicated, is understood to expressly disclose and include any integer and fractional concentrations, percentages, or ratios within that range, such as tenths and hundredths of the integer, and any subranges within the range.

[0102] For example, any numerical range set forth herein for any physical characteristic, including polymer subunits, size, or thickness, is understood to expressly disclose and include, unless otherwise stated, any integer or fraction of an integer within the disclosed range, or any subrange within the disclosed range.

[0103] For purposes of clarity, any element or feature of a method or composition or process described herein can be combined with any other element or feature of any other method or composition or process described herein. Other terms used herein are meant to be defined by their well-known meanings in the art.

[0104] All features of each aspect of the present disclosure apply mutatis mutandis to all other aspects. Each document referred to herein, including but not limited to patents, patent applications, and journal articles, is incorporated herein by reference as if fully set forth in its entirety.

[0105] In order that the disclosure described herein may be more fully understood, the following examples are set forth, it being understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any respect. [Example]

[0106] Example 1 The supersaturation potential of Compound (I) was investigated by mixing 1 mL of drug dissolved in DMSO with 99 mL of FaSSIF-V1 at 37 °C with stirring (Figure 1). At high drug loadings of 500, 1000, or 2000 ppmw (or μg / g or μg / mL), Compound (I) precipitated virtually instantly and reached a steady state of approximately 20 μg / mL or less within 5 minutes. At the final sampling time of 90 minutes, XRPD confirmed the solid to be crystalline Compound (I). For example, at a drug loading of 200 ppmw, approximately 110 μg / mL of drug dissolved within 5 minutes, and at a drug loading of 100 ppmw, approximately 70 μg / mL of drug dissolved by 20 minutes. The situation after desupersaturation was similar to that at higher drug loadings. Overall, Compound (I) appears to be a compound with a fairly low degree of supersaturation due to its very rapid recrystallization into free form Mod A. Low supersaturation can only be maintained for a relatively short period of time.

[0107] Example 2 The following example demonstrates an initial feasibility evaluation of amorphous solid dispersion formulations. Amorphous solid dispersions (ASDs) were first evaluated as potential formulations of Compound (I). Solid dispersion screening was performed by lyophilizing solid Compound (I) with polymers. The miscibility of Compound (I) was tested using Kollidon® VA64, HPMC-AS-LF, Eudragit® L100-55, and HPMC 603 by DSC analysis of the lyophilized material to determine whether the material was amorphous or crystalline. As shown in Table 2, HPMC 603 recrystallized after 3 weeks under stress conditions at a drug loading of 40%. Kollidon® VA64 recrystallized after 5 weeks at drug loadings of 50% and 40%. HPMC-AS-LF and Eudragit® L100-55 remained amorphous even under stress conditions. However, significant impurities were detected in HPMC-AS-LF and Eudragit® L100-55 after 5 weeks under stress conditions by UPLC analysis.

[0108] [Table 2]

[0109] Based on miscibility, stability (5-week stability at 50°C / 75% RH by mDSC), kinetic solubility data (Example 1), and low supersaturation and very rapid recrystallization, the feasibility of an ASD formulation of Compound (I) was deemed very challenging. As a result, the first option was to formulate Compound (I) as a crystal and nanosize the drug crystals to improve bioavailability. The second formulation option, via an amorphous solid dispersion, was deemed very challenging and only beneficial if the drug could be protected in an amorphous form until it reached the absorption site (duodenum, intestine) and released incrementally, maintaining a low enough supersaturation to prevent rapid recrystallization.

[0110] Example 3: Beagle Dog Study The following example shows three beagle PK studies conducted using various formulations containing Compound (I) at 100 mg / dog. The AUC, Cmax, and Tmax data from the three studies are summarized in Table 3. The first dog PK study (Dog Study #1) was conducted to compare spray-dried micronized crystalline drug granules (MSG) and nanocrystalline drug spray-dried granules (NSG) with HPMC-AS-based hot-melt extruded amorphous solid dispersions (HME-ASD). All powders were placed in hard gelatin capsules (HGC). The HME-ASD formulation performed better than MSG and NSG.

[0111] A second dog PK study (Dog Study #2) compared nanocrystalline granules (NSG) fabricated into film-coated tablets (FCT) with spray-dried amorphous solid dispersions (ASD) made with neutral polymers (e.g., HPMC or Soluplus®). PK parameters were comparable between all formulations.

[0112] A third PK study in dogs (Dog Study #3) compared the exposure of HPMC (a neutral polymer)-based amorphous spray granules (ASG) with and without an enteric polymer coating of HPMC-AS-L or HPMC-AS-H. PK parameters were comparable between all formulations.

[0113] From the results of three dog PK studies summarized in Table 3, it was concluded that only amorphous solid dispersions (ASDs) using enteric polymers, e.g., HPMC-AS, provided maximum exposure. Because exposure from ASDs using neutral polymers was similar to nanosized crystalline drug formulations, the approach of spray-dried granulation of nanosized crystalline drug (NSG) was considered another attractive formulation opportunity, especially considering the substantial exposure advantage of NSG over the poor exposure from spray-dried granulation of micronized crystalline drug (MSG).

[0114] [Table 3]

[0115] Example 4: Nanosuspension spray granules and hot melt extrusion The following example demonstrates nanosuspension spray granules (NSG). The median particle size distribution (D50) of unmilled Compound (I) is approximately 50-200 μm. Compound (I) was milled by jet milling to yield a very fine drug product with a D50 of approximately 1-3 μm. A nanosuspension was prepared by mixing 10% jet-milled Compound (I), 2% PVP K30, and 0.1% SLS in water. Nanosuspension spray granules (NSG) were prepared by spray-drying the nanosuspension and additional PVP K30 and SLS onto a sugar core carrier. The NSG was then further blended with extragranular excipients, such as mannitol, lactose, Avicel PH012 (MCC), croscarmellose sodium, crospovidone, silicon dioxide, and steraryl sodium fumarate. The blend was compressed into tablets using a tablet press and film-coated.

[0116] To evaluate the optimal formulation, several batches of NSG tablets were manufactured. Lactose SD and mannitol SD were used as the sugar core of the NSG. Lactose SD, mannitol SD, and microcrystalline cellulose (MCC) were used as excipients, and croscarmellose sodium and crospovidone were evaluated as disintegrants. Table 4 details the excipients used in several batches, and their effect on compaction characteristics was evaluated. Figure 2 shows the effect of excipients on compaction characteristics. The formulation was optimized to achieve a disintegration time of less than 10 minutes at 2 MPa. The ratio of soluble to insoluble excipients was optimized to 40% soluble and 60% insoluble excipients.

[0117] [Table 4]

[0118] See Table 5 for the final configuration of the NSG.

[0119] [Table 5]

[0120] Manufacturing process of nano suspension spray granule tablets: a. A binder, such as polyvinylpyrrolidone (PVP), is dissolved in water under stirring. b. Add a surfactant, such as sodium lauryl sulfate (SLS), to the solution of step a and dissolve under stirring. c. Add compound (I) to the solution from step b and suspend under stirring. d. The suspension from step c is used for grinding using a wet ball mill or the like. e. Dissolve the required amount of SLS and polyvinylpyrrolidone in additional purified water under stirring. f. Weigh out the required amount of the suspension from step d and add it to the solution from step e to complete the suspension for spraying, such as a spray granulation product. g. Add an inert substrate (carrier particle), such as lactose SD or mannitol SD. h. Spray the suspension from step e onto the inert substrate from step g, such as lactose SD or mannitol SD200, to form a spray granulation. i. The granule particles from step h were mixed with an extragranular blend of lactose, microcrystalline cellulose, croscarmellose sodium, silica, and steraryl sodium fumarate. j. The blended mixture of step i was placed into capsules or compressed into tablets.

[0121] Holt melt extrusion (HME) was also attempted to prepare amorphous solid dispersions (ASDs) of compound (I) and different polymers, but this approach had to be quickly abandoned due to the thermal degradation of compound (I), as the compound-polymer mixture had to be extruded at temperatures exceeding 160 °C.

[0122] Example 5: Development of amorphous solid dispersion spray granules The following examples demonstrate the chemical and physical stability of Compound (I) in various polymers when stored for extended periods of time under elevated temperature and various relative humidity conditions. Amorphous solid dispersion (ASD) powders were prepared by spray drying mixtures of Compound (I) and various polymers from organic solutions.

[0123] All powders exhibited good chemical and physical stability when stored at room temperature, e.g., for at least 3 months. However, significant differences were observed when stored at elevated temperatures, as shown in Table 6. In general, impurities increased with temperature, moisture, and time. The highest impurity concentrations were observed in the enteric polymers. HPMC-AS had more impurities than Eudragit L100-55. This could suggest drug degradation in the presence of acidic functional groups, consistent with the previously mentioned instability of the drug in acidic solutions. Although the impurity concentration was low, significant impurity levels were observed in neutral HPMC. Additionally, it appears that increasing the drug and decreasing the polymer can reduce the total amount of impurities. Interestingly, almost no degradation occurred with the neutral polymer Soluplus®. On the other hand, Soluplus® was the only polymer in which Compound (I) recrystallized at 40°C (8 weeks, 75% relative humidity), with more significant recrystallization observed at 60°C. Another undesirable characteristic of Soluplus® was that it softened and the powder turned into hard, sintered plugs at 40°C, 75% relative humidity, or 60°C, 50% relative humidity. Eudragit® L100-55 was observed to sinter the powder and form plugs after storage at 40°C, 75% relative humidity, or 60°C, 11% relative humidity, but no recrystallization was observed. The HPMC-AS powder solidified slightly, and the plugs could be redispersed, but no recrystallization was observed. All HPMC powders remained flowable and showed no signs of recrystallization. TGA results indicated relatively limited moisture absorption, depending on storage conditions, with HPMC-AS exhibiting the lowest level of moisture absorption among the ASD polymers.

[0124] HPMC-based ASG In the next wave of development, the spray-drying process for ASD production was converted to spray granulation, allowing the granules to be coated with an enteric coating. Based on previous experience with chemical and physical stability, HPMC was used as the polymer for ASD or amorphous spray granules (ASG). Other ASG components included mannitol SD as a carrier and a small amount of silica. The drug and polymer were dissolved in acetone / water to prepare the spray solution. Furthermore, a thermal barrier layer of HPMC, silica, and SLS was added to pure ASG by spray granulation, followed by an enteric layer of HPMC-AS-L or HPMC-AS-H. All three types of granules were tested for biological properties in the third canine PK study #3 (described above). There was no significant difference in the exposability of HPMC-based ASG whether coated with a neutral seal layer alone or an enteric layer of HPMC-AS-L or HPMC-AS-H. Furthermore, HPMC-based ASG showed little drug degradation, with total impurities of approximately 0.1%, after 8 weeks at 40°C and 75% relative humidity, whereas enteric-coated ASG showed significant drug degradation, with total impurities of approximately 1.5% and 0.9%, respectively, after 8 weeks at 40°C and 75% relative humidity. In conclusion, the addition of a neutral seal layer did not prevent further drug degradation in combination with HPMC-AS, nor did it improve the biological properties beyond those already provided by the nanocrystal approach.

[0125] HPMC-AS based ASG The final approach was to return to an enteric polymer, i.e., HPMC-AS-based ASD, because its chemical and physical stability appeared acceptable during ambient storage. The manufacturing method was the same as described above, except that the carrier was changed to lactose SD. The spray solution contained approximately 9% solids (Compound (I), HPMC-AS-LF, and silica) dissolved / suspended in a 9:1 (w / w) acetone / water mixture. As expected, the physical and chemical stability of the HPMC-AS-based ASG was not significantly affected by ambient storage for 8 weeks or 4 months. Slightly increased stress storage at 30°C and 75% relative humidity resulted in initial drug degradation after 8 weeks. However, significant drug degradation was observed at 60°C and 11% relative humidity. To ensure shelf life, the degradation level was set at approximately 2%.

[0126] Another drawback of ASG is its residual acetone content of 1.8–2.3%, which is partly reflected in the higher mass loss by TGA compared to HPMC-AS-based ASG. Vacuum drying (approximately 20 mbar) at 50 or 60 °C for approximately 1 day reduced the residual acetone content to levels below 0.5% without noticeable degradation.

[0127] The powder properties of the ASG batch were favorable, exhibiting high bulk density, good flowability, and a moderate PSD. However, various milling methods were required for various purposes. First, hammer milling was performed to adjust the particle size and improve compressibility. There were two main limitations: First, hammer milling resulted in a large amount of material collecting on the sieve, as observed with a 0.2 mm mesh. Second, reducing the particle size, for example, from a median (D50) of 229 μm to a D50 of 155 μm, resulted in a shorter supersaturation period and a spiked drug release, as seen in Figure 3. This is somewhat undesirable, as the goal is to maximize the drug concentration in solution for as long as possible. Figure 3 also shows that increasing the drug loading to 20% for the ASG (versus 35% for the ASD layer) had a negative effect. However, regardless of the observed in vitro dissolution, pin milling was necessary to further improve compressibility or to produce finer granules suitable for oral administration to rodents. For example, pin milling of ASG with various impacts resulted in powders with median particle sizes (D50) of approximately 20–100 μm.

[0128] [Table 6]

[0129] Example 6: PK performance of HPMC-AS ASG in cynomolgus monkeys The following example demonstrates the biological properties of HPMC-AS-based ASG in cynomolgus monkeys. The granules (hammer-milled) were suspended in 50 mM NaH2PO4 buffer (pH 4.6) and administered by oral gavage. A fairly linear increase in exposure (AUC) was observed between 3 and 15 mg / kg, but not proportionally at 50 mg / kg (see Table 7). The latter may have been somewhat confounded by the somewhat incomplete dosing of two of the three animals. However, the significant desupersaturation effect of Compound (I) at higher doses may be an important factor.

[0130] [Table 7]

[0131] Example 7: PK performance of HPMC-AS ASG formulations in Wistar rats The following example demonstrates the biological properties of HPMC-AS-based ASG and confirms the dose-dependent exposure of the final HPMC-AS-based ASG. Pin-milled HPMC-AS-based ASG was suspended in 50 mM NaH2PO4 buffer (pH 4.6) and administered by oral gavage. At a dose of 100 mg / kg, the biological performance of HPMC-AS-based ASG was similar to that of the nanosuspension. However, HPMC-AS-based ASG demonstrated significant performance at 600 mg / kg compared with the limited exposure increase of the nanosuspension at doses of 300 mg / kg or 1000 mg / kg, as shown in Table 8.

[0132] [Table 8]

[0133] Example 8: Manufacturing Process for Amorphous Solid Dispersion Spray Granule and Capsule Formulations The following examples illustrate the manufacturing process for amorphous spray granule formulations of Compound (I).

[0134] Part A. Granules (ASG): 1. Compound (I), silicon dioxide, and HPMC-AS are mixed in a solution of acetone and water. 2. In a suitable container, mix until a visually uniform, fine yellow dispersion is formed. 3. Sift the lactose monohydrate SD. 4. Add the lactose monohydrate SD from step 3 to the fluidized bed granulator and perform fluidized bed granulation with the dispersion from step 2. 5. Mill the fluidized bed granulation product from step 4.

[0135] Part B. Hard Gelatin Capsules (HGC): 1. Add the ingredients to a suitable container: lactose monohydrate SD, Compound (I) granules (from Part A, Step 5), silicon dioxide, croscarmellose sodium, steraryl fumarate sodium, microcrystalline cellulose, and blend. 2. Sift the mixture from step 1. 3. Mix the Step 2 formulation. 4. Encapsulate the final blend from Step 3

[0136] Example 9: Manufacturing Process for Amorphous Solid Dispersion Spray Granule and Tablet Formulations The following examples illustrate the manufacturing process for amorphous spray granule formulations of Compound (I).

[0137] Part A. Granules (ASG): 1. Compound (I), silicon dioxide, and HPMC-AS are mixed in a solution of acetone and water. 2. In a suitable container, mix until a visually uniform, fine yellow dispersion is formed. 3. Sift the lactose monohydrate SD. 4. Add the lactose monohydrate SD from step 3 to the fluidized bed granulator and perform fluidized bed granulation with the dispersion from step 2. 5. Mill the fluidized bed granulation product from step 4.

[0138] Part B. Film-coated tablets (FCT) 1. Add the ingredients to a suitable container: Compound (I) Granules (from Part A, Step 5), silicon dioxide, croscarmellose sodium, steraryl fumarate sodium, microcrystalline cellulose, and blend. 2. Sift the mixture from step 1. 3. Mix the Step 2 formulation. 4. Compress the final blend from step 3 into tablets. 5. Film coat the tablets from step 4.

[0139] Part C. Film-coated tablets (FCT) 1. Add ingredients to a suitable container: Compound (I) Granules (from Part A, Step 5), silicon dioxide, low-substituted hydroxypropyl cellulose (L-HPC), sodium steraryl fumarate, and blend. 2. Sift the mixture from step 1. 3. Mix the Step 2 formulation. 4. Compress the final blend from step 3 into tablets. 5. Film coat the tablets from step 4.

Claims

1. Formula (I) 【Chemical 1】 1. A pharmaceutical composition of a compound of formula (I) comprising said compound of formula (I) stabilized in an amorphous state with a polymer.

2. 10. The pharmaceutical composition of claim 1, wherein said compound of formula (I) is present in about 5-80% by weight, about 10-50% by weight, about 25-40% by weight, or about 30% by weight.

3. 2. The pharmaceutical composition of claim 1, wherein the polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl methylcellulose succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, povidone (PVP), copovidone (PVP VA 64), cellulose acetate, cellulose acetate phthalate, or polyacrylates such as, for example, ammonio methacrylate copolymers (e.g., Eudragit RS / RL), methacrylic acid-ethyl acrylate copolymers (e.g., Eudragit L100 or L100-55), polyvinyl acetate, polyvinyl acetate phthalate, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®).

4. 4. The pharmaceutical composition of claim 3, wherein the polymer is HPMC-AS-L, HPMC-AS-M, HPMC-AS-H, or Eudragit L.

5. Formula (I) 【Chemistry 2】 A pharmaceutical composition of a compound represented by the formula: (i) an intragranular blend, (a) Amorphous spray granules, comprising: (i) a compound of formula (I), wherein said compound exists in amorphous form; and (ii) a polymer; and (b) a suspending agent; and (c) an intragranular blend comprising a carrier; (ii) an extragranular blend, (d) an excipient; and (e) a disintegrant; and (f) a glidant; and (g) a lubricant; and an extragranular blend comprising:

6. (i) an intragranular blend, (a) Amorphous spray granules, comprising: (i) the compound of formula (I), wherein the compound is present in amorphous form in an amount of about 5% to 20% by weight; (ii) a polymer in an amount of about 10% to 60% by weight; and (b) a suspending agent in an amount of about 0.5% to 2.0% by weight; (c) an intragranular blend comprising a carrier in an amount of about 20% to 80% by weight; (ii) an extragranular blend, (d) an excipient in an amount of about 10% to 40% by weight; (e) a disintegrant in an amount of about 0% to 5% by weight; (f) a glidant in an amount of about 0.5% to 2.0% by weight; (g) a lubricant in an amount of about 0.5% to 3.0% by weight, and an extragranular blend comprising:

7. (i) an intragranular blend, (a) Amorphous spray granules, comprising: (i) the compound of formula (I), which is present in amorphous form in an amount of 11.9% by weight; (ii) a polymer in an amount of about 26.6% by weight; and (b) a suspending agent in an amount of about 1.3% by weight; (c) an intragranular blend comprising a carrier in an amount of about 30.3 wt.%; (ii) an extragranular blend, (d) an excipient in an amount of about 24.6% by weight; (e) a disintegrant in an amount of about 2.8% by weight; (f) a glidant in an amount of about 1.0 wt. %; (g) a lubricant in an amount of about 1.5% by weight; and an extragranular blend comprising:

8. The pharmaceutical composition according to any one of claims 5 to 7, wherein the polymer is hydroxypropyl methylcellulose succinate (HPMC-AS).

9. 9. The pharmaceutical composition of claim 8, wherein the hydroxypropyl methylcellulose succinate is selected from hydroxypropyl methylcellulose succinate grade L (HPMC-AS-L), hydroxypropyl methylcellulose succinate grade M (HPMC-AS-M), and hydroxypropyl methylcellulose succinate grade H (HPMC-AS-H).

10. 8. The pharmaceutical composition of claim 7, wherein the suspending agent is silicon dioxide.

11. 8. The pharmaceutical composition of claim 7, wherein the carrier is lactose.

12. 8. The pharmaceutical composition of claim 7, wherein the excipient is lactose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose (L-HPC), or a combination thereof.

13. 8. The pharmaceutical composition of claim 7, wherein the disintegrant is croscarmellose sodium.

14. 8. The pharmaceutical composition of claim 7, wherein the glidant is silicon dioxide.

15. 8. The pharmaceutical composition of claim 7, wherein the lubricant is sodium stearyl fumarate.

16. (i) an intragranular blend, (a) Amorphous spray granules, comprising: (i) the compound of formula (I), which is present in amorphous form in an amount of 11.9% by weight; (ii) amorphous spray granules comprising hydroxypropyl methylcellulose succinate in an amount of about 26.6% by weight; (b) silicon dioxide in an amount of about 1.3 wt. %; (c) lactose in an amount of about 30.3% by weight; and (ii) an extragranular blend, (d) lactose and microcrystalline cellulose in an amount of about 24.6% by weight; (e) croscarmellose sodium in an amount of about 2.8% by weight; (f) silicon dioxide in an amount of about 1.0 wt. %; (g) sodium stearyl fumarate in an amount of about 1.5% by weight; and an extragranular blend comprising:

17. 17. The pharmaceutically acceptable composition of any one of claims 1 to 16, wherein the composition is in the form of a capsule or tablet.

18. (i) Preparation of an amorphous spray granulation, comprising: (a) suspending a compound of formula (I), a polymer, and a suspending agent in an organic solution of acetone containing water; (b) mixing the suspension of (a) to form a dispersion of dissolved compound of formula (I); (c) spraying the dispersion of (b) onto a carrier in a fluid bed dryer to form amorphous spray granules; (ii) preparing an extragranular phase, the extragranular phase comprising: (d) an excipient; and (e) a disintegrant; and (f) a glidant; and (g) a lubricant; (iii) blending the amorphous spray granules (i) and the extragranular phase (ii) to form a final blend.

19. 20. The process for manufacturing a pharmaceutical composition according to claim 18, wherein the composition is filled into a capsule.

20. 20. A process for manufacturing a pharmaceutical composition according to claim 18, wherein the composition is compressed into a tablet.

21. Gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, seminoma or dysseminoma germ cell tumor, mastocytosis, mast cell leukemia, lung adenocarcinoma, lung squamous cell carcinoma, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilia-associated acute bone disease 21. A method of treating a disease selected from the group consisting of myeloid leukemia, lymphoblastic T-cell lymphoma, liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and non-small cell lung cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the composition of any one of claims 1 to 20.

22. 22. The method of claim 21, wherein the disease is non-small cell lung cancer (NSCLC).

23. Gastrointestinal stromal tumor (GIST), NF-1-deficient gastrointestinal stromal tumor, succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor, KIT-driven gastrointestinal stromal tumor, PDGFRA-driven gastrointestinal stromal tumor, melanoma, acute myeloid leukemia, germ cell tumors of seminoma or dysseminoma, mastocytosis, mast cell leukemia, lung adenocarcinoma, lung squamous cell carcinoma, glioblastoma, glioma, pediatric glioma, astrocytoma, sarcoma, malignant peripheral nerve sheath sarcoma, intimal sarcoma, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia 21. Use of the composition of any one of claims 1 to 20 for the preparation of a medicament for the treatment of a disease selected from the group consisting of: eosinophilia-associated acute myeloid leukemia, lymphoblastic T-cell lymphoma, liver cancer, head and neck cancer, esophageal cancer, uterine cancer, breast cancer, bladder cancer, cervical cancer, colorectal cancer, kidney cancer, melanoma, gastric cancer, castration-resistant prostate cancer (CRPC), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and non-small cell lung cancer.

24. 24. The use according to claim 23, wherein the disease is non-small cell lung cancer (NSCLC).

25. Formula (I) 【Chemistry 3】 A pharmaceutical composition of a compound represented by the formula: (i) nano-sized crystalline spray granules, (a) a compound of formula (I) in crystalline form A, wherein said crystals are nanosized; (b) a polymer; and (c) a surfactant; and (d) a carrier; and nano-sized crystalline spray granules comprising: (ii) an extragranular blend, (e) one or more excipients; and (f) a disintegrant; and (g) a glidant; and (h) a lubricant; and an extragranular blend comprising:

26. (i) nano-sized crystalline spray granules, (a) said compound of formula (I), wherein said compound of formula (I) is in nano-sized crystalline form A in an amount of about 5% to about 20% by weight; (b) a polymer in an amount of about 5% to 20% by weight; (c) a surfactant in an amount of about 0.1% to 1.0% by weight; (d) a carrier in an amount of about 20% to 80% by weight; and nano-sized crystalline spray granules comprising: (ii) an extragranular blend, (e) one or more excipients in an amount of about 25% to 50% by weight; (f) a disintegrant in an amount of about 2% to 10% by weight; (g) a glidant in an amount of about 0.5% to about 2.0% by weight; (h) a lubricant in an amount of about 0.5% to about 2.0% by weight.

27. (i) nano-sized crystalline spray granules, (a) the compound of formula (I), wherein the compound of formula (I) is in nano-sized crystalline form A in an amount of 12.5% by weight; (b) a polymer in an amount of about 8.34%; (c) a surfactant in an amount of about 0.25% by weight; (d) a carrier in an amount of about 28.9% by weight; and nano-sized crystalline spray granules comprising: (ii) an extragranular blend, (e) one or more excipients in an amount of about 40% by weight; (f) a disintegrant in an amount of about 6% by weight; (g) a glidant in an amount of about 1.5% by weight; 27. The pharmaceutical composition of claim 26, comprising an extragranular blend comprising: (h) a lubricant in an amount of about 1.5% by weight.

28. The pharmaceutical composition according to any one of claims 25 to 27, wherein the polymer is povidone or copovidone.

29. 29. The pharmaceutical composition of claim 28, wherein the povidone is PVP K30.

30. (i) Crystalline nanospray granules, comprising: (a) the compound of formula (I), wherein the compound of formula (I) is in nano-sized crystalline form A in an amount of 12.5% by weight; (b) povidone in an amount of about 8.34%; (c) sodium lauryl sulfate in an amount of about 0.25% by weight; (d) a lactose carrier in an amount of about 28.9% by weight; and (ii) an extragranular blend, (e) lactose and microcrystalline cellulose in an amount of about 40% by weight; (f) croscarmellose sodium in an amount of about 6% by weight; (g) silicon dioxide in an amount of about 1.5 wt. %; 28. The pharmaceutical composition of claim 27, comprising: (h) an extragranular blend comprising sodium steraryl fumarate in an amount of about 1.5% by weight.

31. 31. The pharmaceutical composition of any one of claims 25 to 30, wherein the crystals of the compound of formula (I), crystalline form A, have a median particle size (D50) of about 150 to 250 nm.

32. (i) mixing a mixture comprising nanosized crystalline form A of the compound of formula (I), a polymer and a surfactant in a liquid medium; (ii) adding the mixture to a carrier to form a dry granulation.

33. 33. The process of claim 32, wherein step (i) is carried out in a wet-milling chamber.

34. 34. The process of claim 32 or 33, wherein the liquid medium is an aqueous solution.

35. A process according to any one of claims 32 to 34, wherein the mixture of step (i) is dispersed on the carrier and dried to form granules.

36. 36. The process according to any one of claims 32 to 35, wherein the process further comprises preparing the final dosage form by blending the granules obtained from step (ii) with an extragranular phase, wherein the extragranular phase comprises one or more excipients, disintegrants, glidants, and lubricants.

37. 37. The process of claim 36, wherein the final dosage form is encapsulated or tableted.

38. 38. The process of claim 37, wherein the final dosage form is compressed into tablets and the resulting tablets are further film coated.

39. A process for preparing a suspension comprising mixing a compound of formula (I), a pharmaceutically acceptable salt thereof, or the free form thereof, at least one polymer, and optionally a surfactant, with a liquid medium.

40. 40. The process of claim 39, wherein the suspension is subjected to wet-milling to reduce the size of the crystals of the compound of formula (I).

41. 41. The suspension of claim 40, wherein the crystals of the compound of formula (I) in the suspension have a median particle diameter (D50) of about 100 nm to 500 nm.

42. 42. The suspension of claim 41, wherein the crystals of the compound of formula (I) in the suspension have a median particle diameter (D50) of about 150 nm to 250 nm.

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